While mammography provides a method for the early detection of breast cancer, there are still breast cancer patients who do not have mammographically detectable lesions. Furthermore, only 25% of women who develop breast cancer have a recognized risk factor. Evaluation of the ductal epithelium of the breast may reveal markers which could identify women who are at an increased risk for developing breast cancer and thereby would derive greater benefit from surveillance or would be appropriate for intervention studies. Breast ductal epithelium is shed into ductal fluid, and this fluid can be aspirated from the nipple in approximately 50-60% of women. Published studies by Petrakis and others have shown that the ability to yield fluid is associated with an increased risk of breast cancer compared to non-yielders, but proliferative cytology alone is not adequate to predict breast cancer occurrence. A protocol will be submitted for a feasibility trial to determine the acceptability of obtaining breast nipple aspirate fluid, to characterize the range of volumes obtained and to develop methods of performing multiple assays of the fluid obtained. Specimens will be examined for expression of markers including IGF-1 or TGF-beta levels, estrogen and progesterone receptors, retinoic acid receptors, erbB-2 expression, carbohydrate antigen expression and others. Breast duct aspirate and breast needle aspirates would be obtained to characterize marker expression detectable in one or both specimen sources for concordance. An intervention trial with tamoxifen is planned in a very high risk population identified by traditional risk factors to determine whether marker expression changes with tamoxifen administration. Serial specimens would be examined for modulation of marker expression in response to the intervention. Pharmacologic investigations are proposed to examine the lowest dose of these agents which are associated with a biologic effect. Women with abnormalities on screening mammography would be stratified by whether biopsy of the abnormality was recommended based on standard clinical practice. The characterization of the association between mammographic findings and biomarker expression should be a useful adjunct to the management of these women. Collaborations with the NIH Nuclear Medicine Department are proceeding to develop a PET mammography unit for structural correlations of biochemical changes in the breast detected by PET scanning. These changes will be evaluated in high risk women and correlated with marker findings.